Histone Demethylase KDM7A Regulates Androgen Receptor Activity, and Its Chemical Inhibitor TC-E 5002 Overcomes Cisplatin-Resistance in Bladder Cancer Cells

Abstract

Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.

Syngeneic model of carcinogen-induced tumor mimics basal/squamous, stromal-rich, and neuroendocrine molecular and immunological features of muscle-invasive bladder cancer

“…Based on retrospective clinical observations, the different molecular subtypes are prognostic of response (1,7,14,38). Recent studies have implicated a variety of pathways that contribute to chemoresistance including long noncoding RNAs (39,40), epigenetic pathways (41-47), miRNAs (48) and androgen signaling (44,(49)(50)(51)(52)(53). Based on previous observation that patients with stroma-rich subtype tumors have better prognosis as compared to those having the basal/squam subtype, the cisplatin response was evaluated in two BURP lines with molecular classifications of stromal-rich (BURP-16SR) and basal/squam (BURP-24BaSq).…”

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

“…The AR interacts with enzymes (cofactors) involved in the regulation of histone methylation, such as lysine-specific demethylase 1 (LSD1), KDM4B, KDM5B, KDM7A, EZH2, SMYD3 and PRMT5. Lee et al, 2020 found that the interaction of AR and KDM7A suggested that this histone demethylase mediated the growth of bladder cancer [21]. Kauffman et al, 2011 previously identified the association of bladder cancer with the ARepigenetic coregulators: LSD1 and members of the Jumonji-domain containing coregulator family (JMJD2).…”

Targeting epigenetic regulators to overcome drug resistance in cancers

“…KDM7A can upregulate AR transcription activity via demethylating H3K27me2, and KDM7A inhibitor TC-E 5002 can significantly reduce cell viability in cisplatin-resistant bladder cancer cell lines. 336 PHF8, also named KDM7B, can enhance the expression of FOXA2, which is essential for the development of neuroendocrine prostate cancer (NEPC) through demethylation modification (Table 3). 337 Besides, PHF8 and HER2 can interact with each other in breast cancer, thus promoting the resistance to trastuzumab and other anti-HER2 drugs by regulating the expression of IL6 (Fig.…”